The first aim of this project is to develop a method to establish a morphological diagnosis of diabetic polyneuropathy and to quantify its degree by studying nerves in a skin biopsy. The second aim is to apply the method to patients who present at the University of Minnesota in quest of a pancreas transplantation (Px). The ultimate objective of the project is to determine whether metabolic stabilization by the PTx halts the neuropathy and allows reinnervation to proceed. These goals should now be possible because of the advances made in visualization of nerves through advances in enzyme-immunohistochemistry. By reacting antisera to specific neuropeptides located in neurons and their peripheral extensions and attachment of different chromagens almost all somatic and autonomic nerve fibers can be visualized. Skin contains slender nerves to sweat glands, to hair follicles and arrector pili (smooth muscle attached to hairs), to blood vessels and others that penetrate the epidermal cells to reach the skin surface. Previous to use of the above methods none of these nerves could be stained in the consistent fashion necessary to accurate diagnosis and follow-up. The thin epidermal nerves had not been demonstrated in human skin. We plan to learn more about the number and locations of nerves in normal skin by studying of skin from different body sites of normal human volunteers. Skin from diabetic volunteers will be studied to learn of the changes that occur in nerves at the skin sites chosen for biopsy. Normal and abnormal features of nerves will be quantified. Skin will first be treated so that nerves can be easily seen in a light microscope with or without fluorescence or a confocal microscope. The tissue will then be analyzed using computerized image analysis for some types of nerves and standard morphometric procedures for other nerves. Lastly, skin from diabetic subjects who seek a PTx will be studied. These patients will undergo skin biopsy before and at 1, 3 and 5 years after PTx to document improvement. The findings in the skin will be correlated with results from several neurophysiological tests. The neurophysiological study of the same patients is ongoing as part of another NIH grant. Because the same patients are studied considerable cost sharing will occur between the two projects.